As a graduate student at the Georgia Institute of Technology, Samirkumar Patel was practicing injections into the white outer layer of rabbit eyeballs ex vivo  when he missed his target by just 100 microns. He had been attempting to create a drug depot that would slowly release medication over time, but he accidentally hit what’s known as the suprachoroidal space — a mistake that would lead to an exciting new drug delivery method for the eye (1).

The area sits between the sclera and the layer of blood vessels called the choroid — but usually, this space doesn’t exist. Most of the time, the sclera and choroid tissues fit right up against each other without leaving any space in between. However, if someone injects a fluid precisely at their interface, as Patel accidentally did, the fluid will open the suprachoroidal space and flow between the two tissues.

Patel and his advisors, chemical engineer Mark Prausnitz and the late vision scientist Henry Edelhauser of Emory University, soon realized that putting a drug into the suprachoroidal space was even better than injecting it into the sclera. “What that allows you to do is target the delivery,” said Prausnitz. “It opens up a whole new door in ophthalmology.”

For drugs that need to access the front of the eye, simple eye drops work great. But to reach the choroid or the retina in the back of the eye, ophthalmologists have had to rely on three methods, each with downsides. Most commonly, they use intravitreal injections that go into the middle of the eye and can be done easily in the office, but injections here can have off-target effects on parts of the eye that don’t need the drug. There’s also an option for invasive retinal surgery, but that carries a risk of damaging the delicate anatomy of the eye. Finally, systemic delivery exposes the whole body to the drug, which can lead to side effects. In contrast, suprachoroidal injections allow ophthalmologists to target the back of the eye specifically without causing potentially harmful side effects — and it’s easy for doctors to perform in the office too. “That's really the beauty of it. … It's such a simple solution,” said Prausnitz. “It enables something that you just couldn't do before.”

With an exciting new ocular drug delivery method on their hands, Patel, Prausnitz, and Edelhauser founded Clearside Biomedical in 2011. In 2021, the FDA approved the company’s combination product Xipere: a steroid drug plus their suprachoroidal space (SCS) Microinjector to treat macular edema associated with uveitis, a buildup of fluid in the retinal layers. This became the first drug delivered into the suprachoroidal space. The company is now working on developing several other drugs that can be delivered to the suprachoroidal space using their SCS Microinjector.

What that allows you to do is target the delivery. … It opens up a whole new door in ophthalmology.
– Mark Prausnitz, Georgia Institute of Technology

“What is important from our perspective is that we are not really a device company, but we are using the device as a platform company to deliver different drugs,” said Victor Chong, Chief Medical Officer, Executive Vice President, and Head of Research and Development at Clearside Biomedical. “What we are trying to do is to develop combination products.”

Testing out the suprachoroidal space 

Xipere delivers the steroid triamcinolone acetonide to the suprachoroidal space. Clinicians commonly deliver this steroid using intravitreal injections, but that delivery mechanism often causes the drug to flow forward into the lens, which could lead to cataracts or increased eye pressure, putting patients at risk of developing glaucoma. “If you want treat retina and choroid disease, then you want the drug to be there rather than spreading all over the place,” said Chong. He explained that clinical trials and post-marketing real-world data have shown that Xipere does not cause meaningful increases in cataracts or eye pressure (2-4).

Chong said that to date, clinicians have used their SCS Microinjector to perform more than 15,000 suprachoroidal injections. He acknowledged that there is a slight learning curve for ophthalmologists who try it out for the first time, but that it’s an easy procedure to do once trained. Chong also emphasized that they developed their SCS Microinjector to be as safe and simple to use as possible. While some other suprachoroidal injection devices from other companies cut into the choroid space and risk bleeding, their SCS Microinjector finds a place in the choroid where there is virtually no blood and senses a slight pressure change that tells the ophthalmologist that they’re in the right place to inject the drug. “That was the so-called magic on our device,” said Chong. “You just feel that the pressure changes, and then you go in the right place. And then when you start injecting slowly, then that space will open up.”

Using this technology, researchers at Clearside Biomedical are now testing suprachoroidal delivery of axitinib, a tyrosine kinase inhibitor, to treat wet age-related macular degeneration (wet AMD). In wet AMD, people lose their vision due to the growth of blood vessels under the retina. Axitinib, which is approved to treat kidney cancer, stops the formation of new blood vessels, so Clearside Biomedical has reformulated it for use in their SCS Microinjector. Last October, the company released results from their Phase 2b study showing that the drug was safe and well-tolerated, and it led to stable disease without the need for a second dose until around six months for 67 percent of patients. Clearside Biomedical announced plans for their Phase 3 trial in March. Their team is also working on developing two additional undisclosed molecules currently in the preclinical stage to treat geographic atrophy, an advanced stage of AMD.

In addition, Clearside Biomedical has partnered with AbbVie and REGENXBIO on a Phase 3 trial that uses suprachoroidal delivery of an adeno-associated virus (AAV) gene therapy to treat diabetic retinopathy and a Phase 2 trial of another AAV gene therapy to treat wet AMD. They are also in the oncology space partnering with Aura Biosciences on a Phase 3 trial to deliver a viral-like drug conjugate via suprachoroidal injection to treat choroidal melanoma.

Yet, Chong noted one limitation of their drug delivery platform so far: biologic drugs. “We have tried that preclinically, but that doesn't quite seem to work,” he said. But, he added, that may have to do with biologic drugs being too water soluble for the suprachoroidal space, though the team may try to address the issue again in the future. “A small company point of view is, well, let's do what we know how to do and can do.”

Gene therapy and gels

Chong sees a bright future for the suprachoroidal delivery of ocular gene therapies, especially those targeting retinal diseases. In 2017, the FDA approved the gene therapy Luxturna to treat a rare inherited retinal disease, but clinicians deliver the drug through a subretinal injection, which requires surgery. Chong said that researchers have also tried intravitreal delivery of gene therapies, but the viral vectors go everywhere in the eye and lead to inflammation. As a result, “that is a great place for suprachoroidal [delivery] for gene therapy,” said Chong.

But delivering gene therapies to the suprachoroidal space can’t get around one challenge that exists for all ocular gene therapies that use viral vectors: the immune system. When viral vectors insert their DNA into cells, the immune system recognizes the viral particles as foreign and initiates an immune reaction that leads to inflammation that could cause vision loss. Peter Campochiaro, an ophthalmologist who leads clinical trials with suprachoroidal delivery of gene therapies at Johns Hopkins University, is developing non-viral vectors in the form of a bioerodible polymer that delivers the gene therapy DNA via nanoparticles. “The vector itself degrades and is gone very quickly, so there's much less potential for immune response,” said Campochiaro. When his team delivered the polymer using suprachoroidal injections in minipigs, they found that it led to the successful expression of a green fluorescent protein there (5).

Rather than pursue suprachoroidal delivery for gene therapies, Prausnitz has been taking his research in a new direction since founding Clearside Biomedical — but one that still prominently features suprachoroidal injections. His team noticed that suprachoroidal injections cause a drop in eye pressure for a few hours afterwards. Since the only treatments for glaucoma focus on lowering intraocular pressure, Prausnitz decided to see if they could develop a novel glaucoma treatment with the benefits of less invasive suprachoroidal delivery. They injected a hydrogel made out of hyaluronic acid into the eyes of nonhuman primates and found that it decreased intraocular pressure for over one month (6). “Now, in the current generation of this, we have kept the pressure down for more than a year, and we’re seeing how long it can go,” said Prausnitz. He and his team plan to move their testing into humans and recently formed a new company to develop the therapy further.

With so many investigations underway to treat a variety of retinal and choroid diseases, the suprachoroidal delivery of ocular drugs is just getting started. Chong said that when he first heard about the new method, he had concerns — just like he did when intravitreal injections first came on the scene. But now, he said, the eye has shown “major resilience” to suprachoroidal injections, and he remains excited for additional approvals of their combined products in the future.

Campochiaro added, “It's a nice additional approach to add to our armamentarium for therapies.”

References

1. Patel, S.R. et al.  Suprachoroidal Drug Delivery to the Back of the Eye Using Hollow Microneedles. Pharm Res  28, 166–176 (2011).
2. Yeh, S. et al.  Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial. Ophthalmology  127, 948–955 (2020).
3. Khurana, R.N. et al.  Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA). Br J Ophthalmol  106, 1139–1144 (2022).
4. Henry, C.R. et al.  Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA). Br J Ophthalmol  106, 802–806 (2022).
5. Zhang, Y. et al.  Ocular RNA nanomedicine: engineered delivery nanoplatforms in treating eye diseases. Trends Biotechnol  42, 1439-1452 (2024).
6. Chung, Y.G. et al.  IOP Reduction in Nonhuman Primates by Microneedle Injection of Drug-Free Hydrogel to Expand the Suprachoroidal Space. Transl Vis Sci Technol  13, 14 (2024).